MYD88 Mutation Status Impacts Overall Survival and Risk of Histological Transformation in Waldenstrom's Macroglobulinemia

Activating mutations in MYD88 and CXCR4 are present in 93-95% and 30-40% of patients with Waldenstrom's Macroglobulinemia (WM), respectively. Mutations in MYD88 trigger NF-KB dependent growth and survival of WM cells through BTK/IRAK, and AKT/ERK through HCK (Yang et al, Blood 2013; 2016). Patients with MYD88 mutations show high levels of response activity to ibrutinib, that targets BTK and HCK, while responses are poor in MYD88^WT patients denoting biological differences between these two subgroups (Treon et al, NEJM 2015). The mutational landscape of MYD88 wild-type (WT) patients is under investigation, though is likely to involve alternative signaling pathways based on transcriptome studies (Hunter et al, Blood 2016). In a previous study, we observed that patients with MYD88^WT were at higher risk of death, while CXCR4 mutation status had no impact on overall survival (Treon et al, Blood 2014). Given the uncommon nature of MYD88^WT WM disease, we sought in this study to investigate the impact of MYD88^WT status in a larger population of WM patients. WHO and WM Consensus guidelines were utilized to establish WM diagnosis, and thorough pathological and laboratory testing was undertaken to exclude non-WM IgM secreting B-cell entities. We utilized sorted CD19⁺ lymphoplasmacytic cells (LPC) obtained from the bone marrow of WM patients, and determined MYD88 mutation status by highly sensitive and specific AS-PCR for MYD88^L265P as before (Xu et al, Blood 2013). Patients with wild-type MYD88 by AS-PCR underwent Sanger sequencing to exclude non-L265P MYD88 mutations as before (Treon et al, NEJM 2015). CXCR4 mutation status was determined in sorted LPC by AS-PCR and Sanger sequencing as before (Xu et al, BJH 2016). We identified 46 MYD88^WT WM patients by these efforts, and compared their findings at time of diagnosis, and survival outcome to 262 patients with MYD88 mutated (MYD88^MUT) disease who were diagnosed over the same time-period. The median follow-up for all patients was 74.7 (0.5-324.9 months), and was similar for MYD88^WT and MYD88^MUT WM patients (64.1 vs. 73.7 months, respectively; p=0.71). Patient characteristics are shown in Table 1.

Among 262 MYD88^MUT patients, 261 had L265P and 1 had the S243N MYD88 mutations; 101 (38.5%) were also CXCR4 mutated. Four (8.6%) MYD88^WT patients were also CXCR4 mutated. During the follow-up period, there were 11 (23.9%) and 15 (5.7%) deaths among the MYD88^WT and MYD88^MUT patients (p=0.003). Figure 1A shows overall survival based on MYD88 and CXCR4 mutation status from time of diagnosis for all patients. The estimated 10-year survival was 73% (95% CI 52-86%) and 90% (95% CI 82-95%) for MYD88^WT and MYD88^MUT patients, respectively (Log-rank p<0.001), and did not differ for MYD88^MUT patients by CXCR4 mutation status (Log-rank p=0.69). Multivariate analysis that included age, gender, serum IgM, hemoglobin, BM disease involvement, serum B2M, MYD88 and CXCR4 mutation status only showed MYD88 mutation status (p<0.001) as a significant determinant for overall survival. Transformation to diffuse large B-cell lymphoma occurred in 7 (15.2%) and 2 (0.76%) of MYD88^WT and MYD88^MUT patients, respectively (p<0.0001), with odds ratio of transformation for MYD88^WT versus MYD88^MUT of 23.3 (95% CI 4.2-233.8; p<0.001). Among MYD88^WT patients who transformed, overall survival was shorter (Figure 1B; Log-rank p=0.08).

Our findings affirm the prognostic significance for MYD88 mutation status as an important determinant of overall survival in WM, and identify a high risk of disease transformation in patients with MYD88^WT disease.

View largeDownload slide

View largeDownload slide

Close modal